Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of oxidatively modified LDL in the pathogenesis of atherosclerosis has been well documented. These studies have focused on modifications of lipid and protein parts of LDL. Recently desialylated LDL has received attention in relation to atherosclerosis and coronary artery disease. We examined the possible involvement of radical reactions in desialylation of LDL. Human LDL was subjected to oxidative damage using Cu2+ ion. As the conjugated dienes monitored by absorption at 234 nm increased, the content of sialic acid decreased steadily. Both the elevation of conjugated diene and the decrease of sialic acid were inhibited by beta-mercaptoethanol, a typical radical scavenger. Besides, both butylated hydroxytoluene and a nitrogen atmosphere inhibited the decrease of sialic acid. These inhibition experiments suggested that sialic acid moieties in LDL were reactive toward radicals.
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PMID:Possible involvement of radical reactions in desialylation of LDL. 928 Feb 82

Oxidatively damaged LDL may play a critical role in the pathogenesis of atherosclerotic vascular disease. Several pathways promote LDL oxidation in vitro but the physiologically relevant mechanisms have proven difficult to identify. Detection of stable compounds that result from specific reaction pathways has provided the first insights into the mechanism of oxidative damage in the human artery wall. Mass spectrometric analysis of protein oxidation products isolated from atherosclerotic tissue implicate tyrosyl radical, reactive nitrogen intermediates and hypochlorous acid in LDL oxidation and lesion formation in vivo. Hypochlorous acid is only generated by the phagocytic enzyme myeloperoxidase, which can also generate tyrosyl radical and reactive nitrogen intermediates. Chiral phase high-pressure liquid chromatography analysis of lipid oxidation products suggests that cellular lipoxygenases may also play a role at certain stages. In contrast, LDL isolated from atherosclerotic tissue is not enriched in protein oxidation products characteristic of free metal ions, which are the most widely studied in vitro model of LDL oxidation. These observations provide the first direct chemical evidence for reaction pathways that promote LDL oxidation in human atherosclerosis.
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PMID:Mechanisms of oxidative damage of low density lipoprotein in human atherosclerosis. 933 50

1. The review summarizes the most important data known so far on chemistry, pharmacodynamics, toxicology and clinics of the investigational agent, pyridoindole stobadine. 2. Stobadine was shown to be able to scavenge hydroxyl, peroxyl and alkoxyl radicals, to quench singlet oxygen, to repair oxidized amino acids and to preserve oxidation of SH groups by one-electron donation. These effects originated from its ability to form a stable nitrogen-centered radical on indole nitrogen. Consequently, it was able to diminish lipid peroxidation and protein impairment under oxidative stress. 3. In various in vitro and in vivo animal models, stobadine was shown to diminish the impairment of the myocardium induced by mechanisms involving reactive oxygen species (e.g., myocardial infarction, hypoxia/ reoxygenation, catecholamine overexposure). 4. The neuroprotective effect of stobadine was demonstrated in a series of in vivo and in vitro models (brain in situ, brain slices, spinal cord, autonomic ganglia, etc.) during ischemia/reperfusion and hypoxia/ reoxygenation or in the presence of chemical systems generating free oxygen radicals, and so forth. Stobadine improved animal survival rate and synaptic transmission recovery, maintained SH tissue level and diminished lipid peroxidation as well as impairment of Ca-sequestering intracellular systems. 5. Oxidation of low-density lipoproteins (LDLs), which plays a major role in the development of atherosclerosis, was decreased by stobadine in vitro. Both lipid and protein (apo B) components of LDL were protected against Cu(2+)-induced oxidation by this agent. 6. Stobadine proved to be an effective protectant in models of free radical pathology in vivo, such as cyclophosphamide-, MNNG- or 60Co-induced mutagenesis and alloxan-induced hyperglycemia. 7. Besides other remarkable pharmacodynamic effects, stobadine exerts antidysrhythmic, local anesthetic, alpha-adrenolytic, antihistaminic, myorelaxant and antiulcerogenic actions. 8. Pharmacokinetic analyses demonstrated that stobadine was readily absorbed from the gastrointestinal tract. Thanks to its balanced lipo-hydrophilic properties, it was distributed over both water and lipid phases in biological tissues. It was shown to easily penetrate the blood-brain barrier. 9. Acute, subchronic and chronic toxicity studies in several animal species, as well as numerous analyses of embryotoxicity, teratogenicity, mutagenicity and genotoxicity, revealed only a negligible toxic potential of this agent. 10. Phase-one clinical study demonstrated safety of the compound. Only slight side effects--namely, a slight hypotension and a slight sedative effect--were observed subsequent to the highest dose used. In phase-two clinical study, the patients with angina pectoris treated for 4 weeks with stobadine showed a significant decrease in the frequency of anginal attacks, in the number of self-administrations of sublingual nitroglycerine and in plasma lipoprotein, cholesterol and triglyceride levels. A slight decrease in systolic and diastolic blood pressure also was observed. 11. It is suggested that stobadine may be considered a contribution to the search for new effective cardio- and neuroprotectants based on antioxidant or free radical scavenging mechanisms of action.
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PMID:Antioxidant and pharmacodynamic effects of pyridoindole stobadine. 955 11

Oxidative damage by reactive nitrogen species has been implicated in the pathogenesis of atherosclerosis and other inflammatory diseases. The mechanisms of tissue damage are poorly understood, however, because the toxic intermediates are short-lived. Previous in vitro studies have suggested that 3-nitrotyrosine represents a specific marker of protein oxidation by reactive nitrogen species. The detection of this nitrated aromatic amino acid may thus serve as an indicator of tissue injury by nitrogen species in vivo. Here we describe a highly sensitive and specific analytical method for quantifying free and protein-bound 3-nitrotyrosine. The assay involves acid hydrolysis of proteins, isolation of 3-nitrotyrosine by ion exchange chromatography, and reduction of 3-nitrotyrosine to 3-aminotyrosine with dithionite. The reduced amino acid is then converted to its n-propyl, per-heptafluorobutyryl derivative and quantified by isotope dilution gas chromatography negative-ion chemical ionization mass spectrometry. Attomole levels of 3-nitrotyrosine can be reproducibly measured in this manner. Quantifying 3-nitrotyrosine levels of tissues by stable isotope dilution gas chromatography/mass spectrometry should provide a powerful tool for exploring the impact of reactive nitrogen species on oxidative reactions in vivo.
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PMID:Isotope dilution mass spectrometric quantification of 3-nitrotyrosine in proteins and tissues is facilitated by reduction to 3-aminotyrosine. 960 53

To measure myocardial blood flow, Nitrogen-13 ammonia. Oxygen-15 water, Rubidium-82 and et al. are used. Each has merit and demerit. By measuring myocardial coronary flow reserve, the decrease of flow reserve during dipyridamole in patients with hypercholesterolemia or diabetes mellitus without significant coronary stenosis was observed. The possibility of early detection of atherosclerosis was showed. As to myocardial metabolism, glucose metabolism is measured by Fluorine-18 fluorodexyglucose (FDG), and it is considered as useful for the evaluation of myocardial viability. We are using FDG to evaluate insulin resistance during insulin clamp in patients with diabetes mellitus by measuring glucose utilization rate of myocardium and skeletal muscle. FFA metabolism has been measured by 11C-palmitate, but absolute quantification has not been performed. Recently the method for absolute quantification was reported, and new radiopharmaceutical 18F-FTHA was reported. Oxygen metabolism has been estimated by 11C-acetate. Myocardial viability, cardiac efficiency was evaluated by oxygen metabolism. As to receptor or sympathetic nerve end, cardiac insufficiency or cardiac transplantation was evaluated. Imaging of positron emitting radiopharmaceutical by gamma camera has been performed. Collimator method is clinically useful for cardiac imaging of viability study.
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PMID:[The review of myocardial positron emission computed tomography and positron imaging by gamma camera]. 964 28

Male Sprague Dawley rats were divided into three groups, viz (I) Controls, (II) High fat diet (HFD) fed, (III) HFD fed+selenium supplemented. After three months of treatment, there were significant increases in serum cholesterol and triglycerides in HFD fed group as compared to control. However, in Se supplemented group, the levels of serum cholesterol and triglycerides were significantly less as compared to group II. Selenium-dependent glutathione peroxidase (GSH-Px) activity in the liver and the aorta increased significantly in HFD fed animals and also showed additional significant increase on selenium supplementation. Malonyldialdehyde (MDA) concentrations in serum, liver and aorta and the activity of nitric oxide synthase (NOS; evident from reactive nitrogen intermediates and citrulline levels) in plasma showed significant increases in HFD fed group. However, supplementation of selenium led to a significant reduction in the levels of these parameters vis-a-vis HFD fed animals except in MDA levels in the serum and the liver where this decrease was non-significant. The important finding of this study is that selenium supplementation modulates the sequences favoring pathogenesis of atherosclerosis.
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PMID:Selenium supplementation and diet induced hypercholesterolemia in the rat: changes in lipid levels, malonyldialdehyde production and the nitric oxide synthase activity. 967 57

A stable HL60 subline having the potential for monocytic differentiation was established by use of GM-CSF. HL60, a human promyelocytic cell line, has frequently been employed for research in the fields of monocytic differentiation and atherosclerosis because of its potential to differentiate into either granulocytes or monocytes. However, HL60 are frequently seen to change their phenotype during long-term culture. To date, many sublines or variants of HL60 cells have been established. However, most of them display diminished or complete loss of activities that characterize parental cells. The present study was conducted to establish a stable HL60 subline with the potential for monocytic differentiation. Firstly, a single HL60 cell was isolated by limiting dilution, and was successfully proliferated by incubation with GM-CSF. Secondly, from this population, cells were selected that had the ability to generate superoxide after VD-induced monocytic differentiation. Cells obtained in this manner (designated HL60/DU-1) exhibited expression of CD14 and CD11b and suppression of CD3 expression after monocytic differentiation. NBT positivity showed a consistent level of over 971% after a 6-day challenge with VD throughout the experimental period of 12 months. HL60/DU-1 cells, which were cryopreserved in liquid nitrogen for 6 months, thawed and re-cultured, exhibited over 97% NBT positivity. Carvedilol and probucol, which exhibit antioxidative activity, inhibited superoxide release from the differentiated HL60/DU-1 cells. HL60/DU-1 cell line is a promising model for the study of monocytic differentiation and the effects of oxygen radicals.
Atherosclerosis 1998 Aug
PMID:Establishment of a stable HL60 subline having the potential for monocytic differentiation using granulocyte-macrophage colony-stimulating factor: possible use for the study of monocytic differentiation and oxidative stress. 971 36

We investigated the association between the serum level of thrombomodulin and known coronary risk factors in 119 men who underwent coronary angiography. Total cholesterol level was significantly higher in patients with coronary atherosclerosis than in those without. Significantly higher frequency of hypertension was noted in patients with coronary atherosclerosis. Uric acid level and frequency of smoking tended to be higher in patients with coronary atherosclerosis but the differences were short short of the significant level. The serum level of thrombomodulin between patients with coronary atherosclerosis and those without was not statistically significant. Age, blood urea nitrogen, and creatinine were positively correlated and creatinine clearance was inversely correlated with the serum level of thrombomodulin. Serum levels of total cholesterol, triglyceride, high-density lipoprotein cholesterol, uric acid, and fasting blood sugar, plasma level of fibrinogen, and body mass index were not related to the serum level of thrombomodulin. There was no significant correlation between the severity of coronary atherosclerosis, hypertension, alcohol use, or smoking and the serum level of thrombomodulin. Restenosis was present in 8 of 16 patients who underwent percutaneous transluminal coronary angioplasty and had a follow-up angiogram at 6.0 +/- 3.0 months. Univariate analysis revealed no significant difference in the thrombomodulin level with and without restenosis. The present findings suggest that elevated thrombomodulin levels in patients with coronary artery disease may reflect retention of thrombomodulin due to decrease in thrombomodulin clearance in the kidney.
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PMID:Thrombomodulin levels in patients with coronary artery disease. 992 5

According to the anoxemia theory of atherosclerosis, an imbalance between the demand for and supply of oxygen and nutrients in the arterial wall is a key factor in atherogenesis. However, the energy metabolic state of the arterial tissue in vivo is largely unknown. We applied a bioluminescence method, metabolic imaging, to study local ATP concentrations in cryosections of normal pig and atherosclerotic and normal rabbit aorta. Some vessels were subjected to energy metabolic restrictions by incubation at different oxygen and glucose concentrations and others were rapidly frozen in liquid nitrogen to reflect the in vivo situation. Local ATP concentrations and the ATP distribution at a microscale was dependent on oxygen as well as glucose concentrations during incubation. ATP depletion was seen in the mid media of pig aorta in all incubations, but only at low oxygen concentration without glucose in the media of the thinner rabbit aorta. ATP-depleted zones were seen deep in pig media (>750 microm from the lumen) and in rabbit plaques (>300 micrometer+ from the lumen) even at high oxygen (pig 75% O2 and rabbit 21% O2) and glucose concentrations (5.6 mmol/L glucose). This observation probably illustrates an insufficient diffusion of glucose, which highlights the importance of studying the conditions for diffusion not only of oxygen but also of other metabolites in the arterial wall. In rapidly frozen vessels the medial ATP concentration was shown to be 0.6 to 0.8 micromol/g wet weight (both pig and rabbit aorta) and in pig aorta a gradient could be seen indicating higher ATP concentrations at the lumenal side. We propose that metabolic imaging, as applied to snap-frozen tissue, may be used to assess the energy metabolic situation in the arterial wall in vivo. The spatial resolution allows the detection of local variations within the arterial tree. However, steep concentration gradients (eg, near the border of the tissue) will be underestimated. The method may be extended to include determinations of glucose and lactate concentrations and will be used in parallel with an established method to assess hypoxia in the arterial wall in vivo.
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PMID:A bioluminescence method for the mapping of local ATP concentrations within the arterial wall, with potential to assess the in vivo situation. 1019 22

Since its initial discovery as an endogenously produced bioactive mediator, nitric oxide (.NO) has been found to play a critical role in the cellular function of nearly all organ systems. Furthermore, aberrant production of .NO or reactive nitrogen species (RNS) derived from .NO, has been implicated in a number of pathological conditions, such as acute lung disease, atherosclerosis and septic shock. While .NO itself is fairly non-toxic, secondary RNS are oxidants and nitrating agents that can modify both the structure and function of numerous biomolecules both in vitro, and in vivo. The mechanisms by which RNS mediate toxicity are largely dictated by its unique reactivity. The study of how reactive nitrogen species (RNS) derived from .NO interact with biomolecules such as proteins, carbohydrates and lipids, to modify both their structure and function is an area of active research, which is lending major new insights into the mechanisms underlying their pathophysiological role in human disease. In the context of .NO-dependent pathophysiology, these biochemical reactions will play a major role since they: (i) lead to removal of .NO and decreased efficiency of .NO as an endothelial-derived relaxation factor (e.g. in hypertension, atherosclerosis) and (ii) lead to production of other intermediate species and covalently modified biomolecules that cause injury and cellular dysfunction during inflammation. Although the physical and chemical properties of .NO and .NO-derived RNS are well characterised, extrapolating this fundamental knowledge to a complicated biological environment is a current challenge for researchers in the field of .NO and free radical research. In this review, we describe the impact of .NO and .NO-derived RNS on biological processes primarily from a biochemical standpoint. In this way, it is our intention to outline the most pertinent and relevant reactions of RNS, as they apply to a diverse array of pathophysiological states. Since reactions of RNS in vivo are likely to be vast and complex, our aim in this review is threefold: (i) address the major sources and reactions of .NO-derived RNS in biological systems, (ii) describe current knowledge regarding the functional consequences underlying .NO-dependent covalent modification of specific biomolecules, and (iii) to summarise and critically evaluate the available evidence implicating these reactions in human pathology. To this end, three areas of special interest have been chosen for detailed description, namely, formation and role of S-nitrosothiols, modulation of lipid oxidation/nitration by RNS, and tyrosine nitration mechanisms and consequences.
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PMID:Pathophysiology of nitric oxide and related species: free radical reactions and modification of biomolecules. 1023 5


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